Activation of liver X receptors inhibits pancreatic islet beta cell proliferation through cell cycle arrest.
OBJECTIVE
Liver X receptors (LXRs) are important transcriptional regulators of lipid homeostasis and proliferation in several cell types. However, the roles of LXRs in pancreatic beta cells have not been fully established. The aim of this study was to investigate the effects of LXRs on pancreatic beta cell proliferation.


METHODS
Gene expression was analysed using real-time RT-PCR. Transient transfection and reporter gene assays were used to determine the transcriptional activity of LXRs in pancreatic beta cells. Cell viability and proliferation were analysed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), DNA fluorometric, BrdU labelling and [(3)H]thymidine incorporation assays. Cell cycle distribution was investigated by flow cytometry analysis. Adenovirus-based RNA interference was used to knockdown LXRalpha, LXRbeta and p27 in MIN6 cells and mouse islets.


RESULTS
We found that both Lxralpha (also known as Nr1h3) and Lxrbeta (also known as Nr1h2) were expressed and transactivated the LXR response element in HIT-T15 and MIN6 cells. Activation of LXRs dose-dependently inhibited pancreatic beta cell viability and proliferation. This was accompanied by beta cell cycle arrest at the G1 phase. Furthermore, LXR activation increased levels of the p27 protein by inhibiting its degradation. Knockdown of p27 reversed these effects of LXR activation on growth inhibition and cell cycle arrest.


CONCLUSIONS
Our observations indicate that LXR activation inhibits pancreatic beta cell proliferation through cell cycle arrest. A well-known regulator of pancreatic beta cell cycle progression, p27, is upregulated and mediates the effects of LXRs on growth inhibition in beta cells. These observations suggest the involvement of aberrant activation of LXR in beta cell mass inadequacy, which is an important step in the development of type 2 diabetes.
Meng
Z X
ZX
Key Laboratory of Human Functional Genomics of Jiangsu Province, Clinical Diabetes Centre of Jiangsu Province, Nanjing Medical University, Nanjing, People's Republic of China.
Nie
J
J
Ling
J J
JJ
Sun
J X
JX
Zhu
Y X
YX
Gao
L
L
Lv
J H
JH
Zhu
D Y
DY
Sun
Y J
YJ
Han
X
X
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002470:Cell Survival; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D050417:Insulin-Secreting Cells / Q000166:cytology*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; C000605211:Nr1h2 protein, mouse; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear